John Cunningham, Ph.D.

Nucleotides are the building blocks of our genetic material and must be replicated every time a cell divides. Chemotherapeutic drugs interfering with nucleotide metabolism exploit this requirement and are a valuable weapon in the oncologist’s arsenal. However, the cytotoxic properties which make these compounds so efficacious in killing cancer cells also wreak havoc on normal proliferating cells and tissues. In order to create the next generation of drugs that inhibit nucleotide metabolism, we must identify novel targets that are specifically required by cancer cell, but not normal cell, proliferation and survival. My discoveries have identified one such target – the enzyme phosphoribosyl pyrophosphate synthetase 2 (PRPS2). PRPS2, and its paralog PRPS1, generate a critical precursor necessary for producing all nucleotides and function as a ‘molecular throttle’ capable of increasing or decreasing the rate at which these genetic building blocks are made. While targeting this metabolic enzyme represents a powerful approach to stymie nucleotide production, the redundancy afforded by the existence of two distinct forms of the same enzyme also presents a phenomenal opportunity for selectively killing cancer cells. In line with this, I have demonstrated that PRPS2, but not PRPS1, is specifically upregulated and required by cancer cells. This is in contrast to normal cells and developing organisms which require PRPS1, but not PRPS2. This proposal seeks to unravel the molecular basis for this selectivity through use of novel mouse models and structure/function studies, thus pinpointing a putative mechanism of action and developing a rational basis for future drug development.